Malaria is a global disease causing >500 million clinical cases and >1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is crucial to discover new classes of drugs for anti-malarial drug design to combat resistant parasites. We propose that antimicrobial peptides (AMPs) may provide the basis of a novel class of antimalarials. AMPs are an essential component of the innate immune system. AMPs display very broad- spectrum action against bacteria, yeast, fungus by specifically disrupting their membranes rather than targeting proteins. Antiparasitic activities are also reported for a number of AMPs and are thought to kill protozoa by a mechanism similar to their mechanism of action against bacteria: interacting with plasma membranes, causing excessive permeability, lysis and death. Specificity for the parasite versus host cell is attributed to differences in phospholipid content and the lack of cholesterol in the protozoan membranes. Importantly, the site of action for AMPs is the plasma membrane and not any specific receptors or intracellular protein targets that can easily mutate to escape drug inhibition. Thus, the development of resistance to AMPs is less likely to occur. However, while AMPs have good antimicrobial activity, problems with tissue distribution and toxicity have presented obstacles to translating this expensive class of peptides into drugs. PolyMedix has developed series of small non-peptidic mimics of these AMPs (SMAMPs), which have robust, broad- spectrum activity against bacteria and markedly lower toxicity in animals. We propose SMAMPs may provide the basis of a novel class of antimalarials against which resistance will be intrinsically difficult to develop. SMAMPs from PolyMedix were tested and several kill Pl. falciparum parasites in culture having submicromolar IC50s and low cytotoxicity. Importantly, the top hits are active against both chloroquine-sensitive and resistant parasite lines. Our hypothesis is that they act through the perturbation of the food vacuole and possibly other parasitic membranes resulting in the rapid lysis of the food vacuole and parasite death. Membrane targets in bacteria for antimicrobials have been associated with a lower likelihood for developing resistance and this will be tested in Pl. falciparum. The goal of this grant is to validate and pursue antimalarial SMAMPs for therapeutic development. The Phase I portion generates proof-of-concept for this class of compounds through in vitro and in vivo efficacy testing. The Phase II segment aims to result in a discovery lead therapeutic candidate(s). Targeting parasite membranes using SMAMPs represents a highly innovative and novel approach to treating parasitic diseases and distinguishes this project from others in the field. Malaria is a global disease causing at least 500 million clinical cases and more than 1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is paramount to discover new classes of drugs for anti- malarial drug design to combat resistant parasites. We propose to develop novel antimalarial therapeutics using small non-peptidic mimics of naturally-occurring antimicrobial peptides. These therapeutics should prove to be potent, active against resistant parasites and display a low incidence of resistance.